The long range objective is the application of theoretical methods to relate the structure to the function of ion channel proteins. In particular, some problems in the physiology of excitable cells are outlined. Electrostatic model calculations designed to elucidate issues in permeation, selectivity and gating are discussed. A general approach to improved molecular dynamics modeling, focusing on developing intermolecular potential functions reliable in a channel environment, is described. Electrostatic model calculations, using a semi-microscopic approach that rigorously accounts for limited molecular features of the ion(s), water molecules and protein charges that surround and form the aqueous pore, are outlined. This method, which is computationally efficient, will be used to provide a physical basis for understanding major differences between cation and anion channels. Cation channels tend to be highly selective and often single file; anion channels generally are measurably permeable to cations and tend to be larger. The approach outlined in this proposal suggests reasons for these differences. Extension of the method to the study of permeation energetics and the influence of site directed mutagenesis in a variety of cation channels (the nicotimc receptor, gramicidin, various peptabiols) is proposed. A new approach to the construction of molecular dynamics potential functions is presented. The procedure, which accurately describes both short range structural forces and intermediate range electrostatics, is designed to generate "phase transferable" potentials, reliable over a wide range of thermodynamic phase space. Both water and hydrated species are structurally very different in the narrow selectivity regions of a channel than in bulk water. Reliable molecular dynamics simulations of channels must account for this difference. "Phase transferable" potential functions, being reliable over extended p-V-T domains, will satisfy this demand. A speculative approach to modeling gating phenomena is described. Based on an elastic bicapacitor, it draws analogies between gating and phase transitions. The model has interesting consequences: a critical gating voltage in a physiological reasonable range; electrical coupling mechanisms that permit large "gating currents" without requiring large transmembrane charge movements, conceivably resolving some apparent paradoxes in the gating properties of potassium and sodium channels. These studies can provide a physical basis for the acts that "gating charges" are large and that the gating assembly is far from the channel pathway.